The setting of RV254 study offers a unique research opportunity to investigate the interactions between HIV-1 and the central nervous system (CNS) at the time of acute HIV infection (AHI). Our NeuroHIV work is guided by the International NeuroHIV Cure Consortium (www.inhcc.net) and executed with academic collaborators at Yale, UCSF, Missouri Institute of Mental Health, Oregon Health Sciences University, Weill Cornell School of Medicine, and University of Hawaii. The study characterizes the participants’ neurological profiles through required neurological examination, mood disorders screening, neurocognitive assessment and optional lumbar punctures and magnetic resonance imaging (MRI) of the brain. Our reports suggest that HIV-1 invades the CNS within days after transmission (PMID: 22551810), leading to the detection of HIV-1, overt parenchymal immune activation and inflammation in the cerebrospinal fluid (CSF) (PMID: 29741638 & 28177966). Abnormal neurological signs (PMID: 27287217), lower neurocognitive performance (PMID: 26509933) and depression symptoms (PMID: 28484888) were also detected in early acute infection. Our recent work on CSF indicates that diversification of HIV-1 replication occurs early in AHI, leading to viral compartmentalization in the CNS (PMID: 31443253). Yet, MRI studies suggest that the neuroinvasion at AHI leads to limited disruptions to microstructural white matter and resting-state functional connectivity (rsFC) in this early period (PMID: 30101063).
Nearly all RV254 participants initiate antiretroviral therapy (ART) within days of AHI diagnosis, offering the cohort the opportunity to examine the CNS benefit of treating HIV-1 infection at the earliest point of infection. CSF studies reveal that the levels of CSF inflammatory markers are significantly reduced by week 24 of ART (PMID: 27819802), and trend towards normalization by week 96 (PMID: 30668739). RV254 participants also show a lower frequency of CSF HIV-1 escape, a phenomenon in which HIV-1 is detectable despite plasma HIV-1 treatment suppression, when compared to individuals who are diagnosed post-AHI and treated during chronic HIV-1 infection (Handoko et al, AIDS in press). The overall picture suggests that treating HIV-1 at the earliest stage of HIV-1 infection leads to reduced parenchymal immune activation and likely smaller pool of activated or infected resident cells in the CNS. The absence of immunodeficiency-related complications observed in these AHI participants, as compared to participants diagnosed and treated during chronic infection, makes RV254 a desirable model to further examine the neuropsychiatric effects of prolonged ART usage. Two reports about the safety profile of Dolutegravir-based ART usage are recently published based on the cohort’s experience (PMID: 31294931 & 31907064).
The neurological data collected before and after analytical treatment interruption (ATI) in several completed HIV-1 cure studies (SEARCH 022, 023, 024 see Completed Studies) has been analyzed. (PMID: 32916708). In RV254 participants, with brief and closely monitored ATI, analysis reveals a lack of adverse CNS effects, except for alteration in basal ganglia choline detected in magnetic resonance spectroscopy (MRS) analysis. These studies provide an important reference for the design of future HIV-1 cure studies that the cohort continues to investigate.
Latest Technologies in Future Studies
Single cell capabilities has been established on-site in Bangkok to allow detailed interrogation of immunologic perturbations in the CNS associated with AHI and cure studies, as well as investigation of HIV-1 persistence in the CNS. Machine learning studies based on RV254 & RV304 data will generate novel insight into pathogenesis of AHI, treatment for the CNS and other systemic complications. Finally, changes ascertainment of data and sociodemographic parameters in the cohort allows for new investigations into the interplay between HIV-1 and substance use in the brain.